title: Frequency dependence in the action of the class III antiarrhythmic drug dofetilide is modulated by altering L-type calcium current and digitalis glucoside.
abstract: We investigated how modulation of L-type calcium current affects the class II antiarrhythmic effect of dofetilide. Action-potential duration (APD) was determined in guinea pig papillary muscle by microelectrode techniques at different stimulation frequencies (0.5-3 Hz). The APD-prolonging effect (deltaAPD) of 10 nM dofetilide was reversed frequency dependent; it was 51 +/- 6 ms at 0.5 Hz and lower at 3 Hz, 21 +/- 3 ms. Either 10 microM diltiazem or 0.1 microM Bay K 8644 (BayK) was added to decrease or increase L-type calcium currents. In the presence of dofetilide + diltiazem, deltaAPD was reduced to 32 +/- 4 ms at 0.5 Hz but not affected at 3 Hz. Conversely, dofetilide + BayK further prolonged deltaAPD to 78 +/- 10 ms at 0.5 Hz but not at 3 Hz. When 10 microM dihydroouabain, a digitalis glucoside, was added to dofetilide, deltaAPD was more pronounced at 0.5 Hz and reduced at 3 Hz. We conclude that the reversed frequency-dependent effect of dofetilide on APD can be modulated by altering L-type calcium currents. With reduced calcium current, the frequency profile is less reversed and more favorable. The similarity of BayK and dihydroouabain in aggravating the reversed frequency-dependent effect of dofetilide is in line with a contribution of intracellular calcium to this reversed rate-dependent profile in the guinea pig ventricle.
authors.affiliation: Medizinische Klinik, Klinik für Herzkreislauferkrankungen, Deutsches Herzzentrum München, Munich, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Gjini
authors.forename: J
authors.initials: J
authors.lastname: Schreieck
authors.forename: M
authors.initials: M
authors.lastname: Korth
authors.forename: S
authors.initials: S
authors.lastname: Weyerbrock
authors.forename: A
authors.initials: A
authors.lastname: Schömig
authors.forename: C
authors.initials: C
authors.lastname: Schmitt
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010042:Ouabain / Q000031:analogs & derivatives* / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D010627:Phenethylamines; D013449:Sulfonamides; C000977:dihydroouabain; D010042:Ouabain; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004110:Diltiazem; C063533:dofetilide; D002118:Calcium